Corticosteroids In Preterm Infants Research Articles

Corticosteroids for the prevention and treatment of bronchopulmonary dysplasia: an overview of systematic reviews.

Corticosteroids for the prevention and treatment of bronchopulmonary dysplasia: an overview of systematic reviews.

Outcomes of postnatal systemic corticosteroids administration in ventilated preterm newborns: a systematic review of randomized controlled trials.

Prolonged mechanical ventilation, commonly used to assist preterm newborns, increases the risk of developing bronchopulmonary dysplasia (BPD). In recent decades, studies have demonstrated that systemic corticosteroids play a significant role in the prevention and management of BPD. In this systematic review of randomized controlled trials (RCTs), we evaluated the association between the administration of systemic corticosteroids in preterm infants and its long-term outcomes, such as neurodevelopment, growth, extubation rate, and related adverse effects. We conducted an electronic search in Medline, Scopus, and PubMed using the following terms: "premature infants" and "corticosteroids." We considered all RCTs published up to June 2023 as eligible. We included all studies involving preterm newborns treated with systemic corticosteroids and excluded studies on inhaled corticosteroids. A total of 39 RCTs were evaluated. The influence of steroids administered systemically during the neonatal period on long-term neurological outcomes remains unknown, with no influence observed for long-term growth. The postnatal administration of systemic corticosteroids has been found to reduce the timing of extubation and improve respiratory outcomes. Dexamethasone appears to be more effective than hydrocortisone, despite causing a higher rate of systemic hypertension and hyperglycemia. However, in the majority of RCTs analyzed, there were no differences in the adverse effects related to postnatal corticosteroid administration. Dexamethasone administered during the neonatal period appears to be more effective than hydrocortisone in terms of respiratory outcomes; however, caution should be taken when administering dexamethasone. Data derived from current evidence, including meta-analyses, are inconclusive on the long-term effects of the administration of systemic steroids in preterm infants or the possibility of neurodevelopmental consequences.

Postnatal Corticosteroids to Prevent or Treat Chronic Lung Disease Following Preterm Birth.

The American Academy of Pediatrics continues to provide guidance on the use of postnatal corticosteroids to manage or prevent chronic lung disease following preterm birth (formerly referred to as bronchopulmonary dysplasia). Since the last revision of such guidance in 2010, several prospective randomized trials have been published. This revision provides a review of those studies as well as updated recommendations, which include the use of systemic low-dose corticosteroid in preterm neonates with or at high risk for chronic lung disease. High-dose dexamethasone (≥0.5 mg/kg per day) is not recommended. New evidence suggests that inhaled corticosteroids may confer benefit if provided with surfactant as a vehicle, but safety data are lacking. Evidence remains insufficient to make any recommendations regarding routine use of postnatal corticosteroids in preterm infants. Neonatologists and other hospital care providers must continue to use their clinical judgment in individual patients, balancing the potential adverse effects of corticosteroid treatment with those of chronic lung disease. The decision to use postnatal corticosteroids for this purpose should be made together with the infant's parents, and the care providers should document their discussions with parents in the patient's medical record.

Intravenous pulses of methylprednisolone for infants with severe bronchopulmonary dysplasia and respiratory support after 3 months of age.

There are few published data on the efficacy of systemic corticosteroids in preterm infants with very severe forms of bronchopulmonary dysplasia (BPD), requiring respiratory support after 3 months of age. The aim of this study was to report the use of pulses of methylprednisolone in this population and its consequences on the level of respiratory support. This retrospective monocentre study included infants over 3 months of age with severe BPD who received at least one pulse of methylprednisolone (300 mg/m2 /day intravenous [IV] over 3 days). The primary outcome was the evolution of the pulmonary severity score (PSS) during the 3 months preceding and the 5 months following the first pulse. The evolution of the median PSS over time was analyzed using linear segmented regression for interrupted time series. Ten infants were included. During the 3 months preceding the first pulse, a significant increase in the median PSS was observed (p = .01), followed by a progressive decrease during the 5 months after administration of the first pulse (p < .01). Greater effects were observed in more severe infants requiring mechanical or noninvasive ventilation than in those receiving supplemental oxygen through nasal cannula. High-dose IV pulses of methylprednisolone were associated with a decrease in the level of respiratory support required by infants with very severe forms of BPD, with a greater effect in those on mechanical or noninvasive ventilation. Further studies are warranted to confirm these preliminary results and assess the long-term safety of this therapy.

Genetic variation in CRHR1 is associated with short-term respiratory response to corticosteroids in preterm infants at risk for bronchopulmonary dysplasia.

BackgroundBronchopulmonary Dysplasia (BPD) is an orphan disease and advances in prevention and treatment are lacking. Clinical efficacy of systemic corticosteroid therapy to reduce the severity of lung disease and BPD is highly variable. Our objective was to assess whether candidate SNPs in corticosteroid metabolism and response genes are associated with short-term phenotypic response to systemic corticosteroids in infants at high risk for BPD.MethodsPharmacogenetic analysis of data from a large randomized controlled trial (TOLSURF) in infants treated with dexamethasone or hydrocortisone using multivariate linear regression. The primary outcome was change in Respiratory Severity Score (RSS, mean airway pressure × FiO2) at day 7 of corticosteroid treatment.Resultsrs7225082 in the intron of CRHR1 is significantly associated with the magnitude of decrease in RSS 7 days after starting treatment with systemic corticosteroid (meta-analysis p=2.8×10−4). Each T allele at rs7225082 is associated with a smaller absolute change in RSS at day 7, i.e. less response to systemic corticosteroids.ConclusionGenetic variability is associated with corticosteroid responsiveness with regard to respiratory status in preterm infants. Identification of genetic markers of corticosteroid responsiveness may allow for therapeutic individualization, with the goal of optimizing the risk to benefit ratio for an individual child.

Evaluating the use of corticosteroids in preventing and treating bronchopulmonary dysplasia in preterm neonates.

Approximately 15 million babies worldwide are born premature, and complications of prematurity are one of the leading causes of death in neonates. Neonatal respiratory distress syndrome (NRDS) and bronchopulmonary dysplasia (BPD) are two of the most common and serious consequences of prematurity. Synthetic corticosteroids, including dexamethasone, have been central in efforts to treat and prevent BPD. There is strong evidence to show that prenatal corticosteroids reduce infant mortality and the incidence of NRDS, leading to their widespread use in obstetric units. However, data suggest that they are not as effective in reducing the incidence of BPD as NRDS, which may be due to the multifactorial pathogenesis of BPD. On the other hand, the use of postnatal corticosteroids in preterm infants is much more controversial. They have been shown to improve lung function and help in reducing the need for mechanical ventilation. These benefits, however, are associated with a range of adverse short- and long-term effects. This review will discuss the benefits and consequences of corticosteroids in treating BPD and will examine alternative treatments and future research that may improve the understanding of BPD and inform clinical practice.

Efficacy and safety of pulmonary application of corticosteroids in preterm infants with respiratory distress syndrome: a systematic review and meta-analysis

BackgroundSystemic corticosteroids as the frontline treatment of respiratory distress syndrome (RDS) in preterm infants are associated with adverse effects on growth and neurodevelopmental outcome, but the pulmonary administration of steroids...

Corticosteroids for the prevention of bronchopulmonary dysplasia in preterm infants: a network meta-analysis

ObjectiveTo determine the comparative efficacy and safety of corticosteroids in the prevention of bronchopulmonary dysplasia (BPD) in preterm infants.Study designWe systematically searched PubMed, EMBASE and the Cochrane Library. Two reviewers...

Antenatal magnesium for preterm delivery reduces risk of cerebral palsy among surviving very preterm infants.

Commentary on: Rouse DJ, Hirtz DG, Thom E, Varner MW, Spong CY, Mercer BM, Iams JD, Wapner RJ, Sorokin Y, Alexander JM, Harper M, Thorp JM Jr, Ramin SM, Malone FD, Carpenter M, Miodovnik M, Moawad A, O'Sullivan MJ, Peaceman AM, Hankins GD, Langer O, Caritis SN, Roberts JM. Eunice Kennedy Shriver NICHD Maternal-Fetal Medicine Units Networks. A randomized, controlled trial of magnesium sulfate for the prevention of cerebral palsy. N Engl J Med 2008; 359(9):895–905. PMID 18753646. The current American College of Obstetricians and Gynecologists (ACOG) Committee Opinion supports the use of magnesium sulphate for foetal neuroprotection before 32 weeks of gestation 1. The clinical trial reviewed here is the largest and most recent to inform these guidelines 2. This randomised control trial (RCT), aimed to determine if the administration of magnesium sulphate to women at high risk of preterm delivery would reduce the risk of cerebral palsy (CP), found a reduction in moderate/severe CP at two years of age following antenatal magnesium sulphate exposure (RR 0.55, 95% CI 0.32–0.95) 2. These results were consistent with previous RCTs primarily evaluating the neuroprotective benefits of magnesium sulphate on the incidence of CP in preterm infants 3-5. Additionally, a Cochrane review concluded that 63 women were needed to prevent one diagnosis of CP 6. Further investigation is warranted to provide updated and unified guidelines regarding the use of magnesium sulphate for foetal neuroprotection. There was significant heterogeneity in treatment regimens between RCTs with no trial sharing the same loading dose, treatment dose, duration of dosing or retreatment regimen of magnesium sulphate 2-6. Additionally, although no serious maternal complications of antenatal magnesium exposure have been reported, there were several minor complications, including a 50% increase in maternal hypotension, leading to a 3.2-fold increase in cessation of therapy 6. Optimal treatment regimens would likely lead to a refined understanding of treatment effect size, better protocol adherence, and ultimately improved neurodevelopmental outcomes. The results of this trial should be considered in the context of advances in neonatal medicine affecting neurodevelopmental outcomes. Specifically, during the time of this study's enrolment, the American Academy of Pediatrics (AAP) recommended against routine use of postnatal corticosteroids in preterm infants because of its negative effect on neurodevelopmental outcomes 7. This recommendation significantly curtailed the use of early postnatal steroids, potentially altering neurodevelopmental outcomes if differed between treatment groups 7. Additionally, there has been increased survival of infants 22–23 weeks of gestation 8. Currently, there are no RCTs that investigate the neuroprotective benefit of magnesium sulphate in <24 weeks of gestation. It has been 20 years since recruitment started and nearly 10 years since the publication of this landmark trial has influenced the practice of obstetricians in the United States 2. In that same time, there continue to be advances in the care of extremely low birthweight infants impacting changes in survival and neurodevelopmental outcomes. Although many institutions follow ACOG recommendations of administering antenatal magnesium sulphate in preterm delivery, there are no recommendations for magnesium sulphate treatment regimens or gestational age thresholds presumably leading to a variety of clinical practices 1. Perhaps it is time to repeat this clinical trial in a new era to help elucidate both the optimal treatment regimen as well as the effect of antenatal magnesium exposure in the setting of preterm labour and delivery on neurodevelopmental outcomes. In the meantime, this trial remains consistent with available evidence supporting antenatal magnesium sulphate exposure in preterm infants to reduce CP. https://ebneo.org/2017/10/antenatal-magnesium-for-preterm-delivery-reduces-risk-of-cerebral-palsy-among-surviving-very-preterm-infants/ None. None.

Systemic corticosteroid regimens for prevention of bronchopulmonary dysplasia in preterm infants.

Cochrane systematic reviews show that systemic postnatal corticosteroids reduce the risk of bronchopulmonary dysplasia (BPD) in preterm infants. However, corticosteroids have also been associated with an increased risk of neurodevelopmental impairment. It is unknown whether these beneficial and adverse effects are modulated by differences in corticosteroid treatment regimens. To assess the effects of different corticosteroid treatment regimens on mortality, pulmonary morbidity, and neurodevelopmental outcome in very low birth weight (VLBW) infants. We used the standard search strategy of the Cochrane Neonatal Review group to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 2) in the Cochrane Library (searched 21 March 2016), MEDLINE via PubMed (1966 to 21 March 2016), Embase (1980 to 21 March 2016), and CINAHL (1982 to 21 March 2016). We also searched clinical trials' databases, conference proceedings, and the reference lists of retrieved articles for randomized controlled trials. Randomized controlled trials (RCTs) comparing two or more different treatment regimens of systemic postnatal corticosteroids in preterm infants at risk for BPD, as defined by the original trialists. Studies investigating one treatment regimen of systemic corticosteroids to a placebo or studies using inhalation corticosteroids were excluded. Two authors independently assessed eligibility and quality of trials and extracted data on study design, participant characteristics and the relevant outcomes. We asked the original investigators to verify if data extraction was correct and, if possible, to provide any missing data. The primary outcomes to be assessed were: mortality at 36 weeks' postmenstrual age (PMA) or at hospital discharge; BPD defined as oxygen dependency at 36 weeks' PMA; long-term neurodevelopmental sequelae, including cerebral palsy, measured by the Bayley Mental Developmental Index (MDI); and blindness or poor vision. Secondary outcomes were: duration of mechanical ventilation and failure to extubate at day 3 and 7 after initiating therapy; rescue treatment with corticosteroids outside the study period; and the incidence of hypertension, sepsis and hyperglycemia during hospitalizations. Data were analyzed using Review Manager 5 (RevMan 5). We used the GRADE approach to assess the quality of evidence. Fourteen studies were included in this review. Only RCTs investigating dexamethasone were identified. Eight studies enrolling a total of 303 participants investigated the cumulative dosage administered; three studies contrasted a high versus a moderate and five studies a moderate versus a low cumulative dexamethasone dose.Analysis of the studies investigating a moderate dexamethasone dose versus a high-dosage regimen showed an increased risk of BPD (typical risk ratio (RR) 1.50, 95% confidence interval (CI) 1.01 to 2.22; typical risk difference (RD) 0.26, 95% CI 0.03 to 0.49; number needed to treat for an additional harmful outcome (NNTH) 4, 95% CI 1.9 to 23.3; I² = 0%, 2 studies, 55 infants) as well as an increased risk of abnormal neurodevelopmental outcome (typical RR 8.33, 95% CI 1.63 to 42.48; RD 0.30, 95% CI 0.14 to 0.46; NNTH 4, 95% CI 2.2 to 7.3; I² = 68%, 2 studies, 74 infants) when using a moderate cumulative-dosage regimen. The composite outcomes of death or BPD and death or abnormal neurodevelopmental outcome showed similar results although the former only reached borderline significance.There were no differences in outcomes between a moderate- and a low-dosage regimen.Four other studies enrolling 762 infants investigated early initiation of dexamethasone therapy versus a moderately early or delayed initiation and showed no significant differences in the primary outcomes. The two RCTs investigating a continuous versus a pulse dexamethasone regimen showed an increased risk of the combined outcome death or BPD when using the pulse therapy. Finally, two trials investigating a standard regimen versus a participant-individualized course of dexamethasone showed no difference in the primary outcome and long-term neurodevelopmental outcomes.The quality of evidence for all comparisons discussed above was assessed as low or very low, because the validity of all comparisons is hampered by small samples of randomized infants, heterogeneity in study population and design, non-protocolized use of 'rescue' corticosteroids and lack of long-term neurodevelopmental data in most studies. Despite the fact that some studies reported a modulating effect of treatment regimens in favor of higher-dosage regimens on the incidence of BPD and neurodevelopmental impairment, recommendations on the optimal type of corticosteroid, the optimal dosage, or the optimal timing of initiation for the prevention of BPD in preterm infants cannot be made based on current level of evidence. A well-designed large RCT is urgently needed to establish the optimal systemic postnatal corticosteroid dosage regimen.

Corticothérapie postnatale chez le prématuré : étude des pratiques des centres français de néonatologie en 2006

In 1999, 80% of French neonatal centers used corticosteroids, mainly betamethasone (BMT), to prevent or treat bronchopulmonary dysplasia (BPD) [Lee SK, McMillan DD, Ohlson A, et al. Variations in practice and outcomes in the canadian NICU Network 1996-1997. Pediatrics 2000;106:1070-9]. As many data suggested a low risk-benefit ratio, an updated assessment of this use was necessary [Desnoulez L, Empana J, Anceschi M, et al. Prise en charge de l'immaturité pulmonaire en néonatologie : enquête sur les pratiques européennes. Arch Pediatr 2005;12:4-9; Halliday HL, Ehrenkranz RA, Doyle LW. Early postnatal (less than 96h) corticosteroids for preventing chronic lung disease in preterm infants. Cochrane Database Syst Rev 2003:CD001146; Yeh TF, Lin YJ, Lin HC, et al. Outcomes at school age after postnatal dexamethasone therapy for lung disease of prematurity. N Engl J Med 2004;350:1304-13; Lin YJ, LKin CH, Wu JM, et al. The effects of early postnatal dexamethasone therapy on pulmonary outcome in premature infants with respiratory distress syndrome: a 2-year follow-up study. Acta Paediatr 2005;94:310-16]. Questionnaires addressing the use of and indications for corticosteroids were sent to all French neonatal centers. The study was conducted over 5 months (July to November 2006). Of 202 questionnaires sent out, 186 (92%) were completed. Of these 186 centers, 147 (79%) had a standard protocol for corticosteroid use, covering systemic and inhaled steroids (76 units), only systemic steroid therapy (30 units) and only inhaled steroids (41 units). Systemic corticosteroids were used in 106 centers for hemodynamic purposes in 42 cases (40%), prevention of BPD in 1 case (1%), early treatment of BPD (day 4 to day 21) in 23 cases (22%) and late treatment of BPD (after day 21) in 74 cases (70%). Hemisuccinate hydrocortisone (HSHC) was the only corticoid used for hemodynamic failure. The steroid used for early treatment of BPD was BMT (21 out of 23). The duration of treatment was less than 4 days in 10 centers (43%). The steroid most often used for late treatment was BMT (67 out of 74). The duration of treatment was less than 4 days in 29 centers, between 4 and 8 days in 22 centers, and longer than 8 days in 26 centers. Among 117 centers administering corticosteroids by inhalation, 74% used budesonide. Use of corticosteroids was higher in teaching hospitals (86%) than in others (49%), likely due to the immaturity of the neonates hospitalized in these centers. We showed a still frequent use of corticosteroids in preterm infants in France but only after the fourth day of life to treat BPD and not as a prevention therapy. We also found a marginal use of DXM in accordance with both short-term and long-term adverse side effects, suggesting an unbalanced risk-benefit ratio even though it has a beneficial effect on respiratory status. Our findings indicate the need for national recommendations and trials to assess oral BMT treatment in premature neonates with BPD.

Hypertrophic Cardiomyopathy in Preterm Infants Treated With Methylprednisolone for Bronchopulmonary Dysplasia

To the Editor.Glucocorticoids, and in particular dexamethasone, have been used extensively in the prophylaxis and treatment of bronchopulmonary dysplasia in preterm infants. In fact, extensive studies have proven that dexamethasone, given early (<96 hours of life)1 or moderately early (7–14 days of life),2 is effective in reducing the combined frequency of bronchopulmonary dysplasia and mortality. Unfortunately, such effect is associated with numerous adverse effects such as hyperglycemia, hypertension, hypertrophic cardiomyopathy, psychomotor development delay, and cerebral palsy. In particular, the relative risk for the development of hypertrophic cardiomyopathy is 4.39 (95% confidence interval: 1.40–13.37) in infants who received early dexamethasone treatment1 and 14.3 (95% confidence interval: 1.20–67.69) in infants who received moderately early dexamethasone treatment.2Therefore, the American Academy of Pediatrics advised against the treatment with dexamethasone of infants with birth weights <1500 g (very low birth weight [VLBW]), recommended to limit its use to exceptional clinical circumstances and carefully designed randomized, controlled trials, and suggested the opportunity of following clinical trials investigating the use of alternative antiinflammatory corticosteroids.3 Accordingly, we started to treat VLBW preterm infants on maximal ventilatory and oxygen support (median arterial/alveolar oxygen ratio: 0.09; range: 0.07–0.11) with a 12-day tapering course of methylprednisolone given intravenously every 6 hours (0.6, 0.4, 0.2, 0.1 mg/kg per dose for 3 days each).4 From January 1, 2003, to June 30, 2005, we treated with methylprednisolone 10 preterm infants (median gestational age: 24 weeks [range: 23–26 weeks]; median birth weight: 620 g [range: 430–730 g]) affected by respiratory distress syndrome and mechanically ventilated at the median postnatal age of 16.5 days (range: 9–44 days). These patients did not present adverse effects from steroid treatment other than hyperglycemia (1 case) and hypertrophic cardiomyopathy. In fact, echocardiographic study showed in 4 patients (40%) a thickening of the intraventricular septum (reference value: 1.8–4.5 mm) that ranged between 5 and 7 mm (median value: 6 mm) and was associated in 2 cases with a mild thickening of the posterior left ventricular free wall, without an impairment of left ventricular outflow. No pharmacologic therapy was necessary for these patients. However, methylprednisolone was discontinued immediately (median treatment duration: 8.5 days; range 7–10 days), and the pathologic echocardiographic findings disappeared after a median period of 26 days (range: 22–32 days). Among the methylprednisolone-treated infants, 6 (60%) survived, including 3 infants who developed hypertrophic cardiomyopathy.We compared the occurrence of hypertrophic cardiomyopathy with that found in preterm VLBW infants affected by respiratory distress syndrome who did not receive steroid treatment (n = 20) or who were treated with dexamethasone. These infants were randomly selected between those who were born immediately before of after infants treated with methylprednisolone. We found that hypertrophic cardiomyopathy was strongly more frequent in methylprednisolone-treated versus untreated infants (40% vs 0%; P < .0001, calculated by using Fisher's Exact Test) but was similar in methylprednisolone- versus dexamethasone-treated infants (40% vs 20%; P < .3149).Methylprednisolone may represent a possible alternative to dexamethasone in preventing or treating bronchopulmonary dysplasia. However, we found a strong association between the treatment with methylprednisolone and the development of hypertrophic cardiomyopathy in VLBW preterm infants at risk for bronchopulmonary dysplasia.The mechanisms of cardiac hypertrophy resulting from corticosteroid therapy remain unclear, as do those of neurodevelopment injury associated with dexamethasone treatment. Moreover, actual knowledge does not permit evaluating the eventual pathophysiological correlation between cardiac and brain damage. Thus, it cannot be excluded that, similar to dexamethasone, methylprednisolone can exert detrimental adverse effects on both the heart and central nervous system in preterm infants.For these reasons we suggest that, in planning future clinical trials to investigate the use of corticosteroids in preterm infants, those making the choice of drug take into account all of its reported adverse effects. From this point of view, methylprednisolone and dexamethasone similarly induce the occurrence of hypertrophic cardiomyopathy in preterm infants with respiratory distress syndrome.

Postnatal corticosteroids in preterm infants: systematic review of effects on mortality and motor function.

Postnatal corticosteroid therapy has been proved in randomized controlled trials to reduce ventilator dependence and the rate of chronic lung disease in preterm infants with few serious short-term side effects. However, there are other consequences that might follow postnatal corticosteroid therapy that are more important, including mortality or cerebral palsy. To review the evidence from reported randomized controlled trials on the effects of postnatal corticosteroid on long-term mortality and motor dysfunction, including cerebral palsy. The methods involved a meta-analysis of reported randomized controlled trials, following guidelines of the Cochrane Collaboration, including calculation of event rate differences (ERD) and 95% confidence intervals (CI). The mortality rate difference was non-significant both statistically and clinically (ERD - 0.1% favouring corticosteroids, 95% CI -2.9% to 2.8%). There were no subgroups in which a beneficial effect of postnatal corticosteroids on survival could be demonstrated. The rate of motor dysfunction in survivors was significantly higher in survivors from the postnatal corticosteroid group (ERD 11.9% favouring controls, 95% CI 4.6% to 19.2%). The rate of survival, free of motor dysfunction, was significantly lower in the postnatal corticosteroid group (ERD 7.8% favouring controls, 95% CI 0.5% to 15.1%). Although postnatal corticosteroids have short-term benefits, they do not increase the survival rate, and they may cause motor dysfunction in survivors. A large-scale, placebo-controlled randomized trial, with survival free of sensorineural impairments and disabilities as the major endpoint, is urgently needed.

Postnatal Corticosteroids in Preterm Infants - Effects on Mortality and Cerebral Palsy

Postnatal Corticosteroids in Preterm Infants - Effects on Mortality and Cerebral Palsy